tbuckley/cabot-search huggingface dataset:
Establishment of PD3D models of sarcomas: A promising preclinical tool for improvement of sarcoma treatment.
Authors: Manuela Regenbrecht, Rica Sauer, Maya Niethard, Christian RA Regenbrecht, Jürgen Loskutov
Journal: Journal of Clinical Oncology (2022)

e23538 Background: Compared to the progress in understanding and treating carcinomas in the past decade, the options and related clinical benefit in terms of response rates and overall survival for sarcoma patients lacks behind. Increasing incidence, low 5-year-survival rates and nearly endless heterogeneity of sarcomas are challenging oncologists every day. The necessity of so far missing representative preclinical models is obvious. PD3D cell culture models have already proven to be a useful tool to reverse clinical engineer patient outcome in carcinomas. Here we report the establishing and refining of PD3D models for the plethora of sarcoma entities. Methods: We obtained viable sarcoma tissue samples from incisional biopsies or tumor resections. We continuously optimized media conditions. For quality control and pathological evaluation, we embedded the cells in FFPE, stained patient-specific models according to original tumor samples and evaluated them pathologically. Upon histopathological evaluation, we performed semi-automated drug response assays on patient-specific models with up to 12 drugs and drug combinations, including standard of care drugs plus a selection of additional drugs. In the fashion of a prospective observatory study, we compared the results from the in vitro screen with the actual clinical outcome. Results: More than 25 patient derived 3D-cell culture models have been established from various subtypes of sarcomas. Optimized media conditions and sampling operation improved the take rates from ca. 10 to 80% irrespective of the tumor subtype. Pathological examination of the models confirmed original diagnoses and revealed that the patient-specific models recapitulate the key properties of the original tumor. Negative predictive value of drug sensitivity testing was close to 100 %, while the positive predictive value was &gt; 80 %. These results in a limited number of cases puts the predictive value en par with recently published data about the predictive value of patient-derived organoids in carcinomas. Conclusions: Patient derived 3D-cell culture models of sarcomas can be routinely established, irrespective of subtype Models can be used for multi-omics analyses including drug sensitivity screenings Pretherapeutic drug sensitivity screenings could support clinical decision making Findings need to be confirmed in a prospective observatory trial.
EPEN-09. Multi-omics characterization of the blood-brain barrier in molecular groups of ependymoma
Authors: Julia K Sundheimer, Julia Benzel, Cornelia Gansert, Britta Statz, Christian Seitz, Stefan M Pfister, Kendra K Maaß, Kristian W Pajtler
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: A major challenge in the treatment of brain tumors is the limited penetration of many drugs through the blood-brain barrier (BBB). BBB characteristics include endothelial cells connected by tight junction proteins (e.g. Claudin5) and expression of efflux transporters (e.g.P-gp) with the physiological role to limit the accumulation of potentially toxic substances in brain tissue. While BBB permeability shows anatomical region-specific characteristics and changes with age, brain tumors can also impact its integrity. To achieve therapeutically relevant drug concentrations in the tumor, characterization of the pathophysiological BBB is fundamental when developing (pre)clinical trials. Our study seeks to increase our understanding of the BBB composition in various molecular groups of ependymoma. RESULTS: Transcriptional BBB characteristics were assessed for primary ependymoma (n=440), cell lines (n=3), mouse models (n=22), and healthy brain controls (n=200). T-distributed stochastic neighbor embedding (tSNE)-based clustering analyses based on most relevant tight junction and efflux transporter gene sets revealed distinct molecular ependymoma group-specific expression patterns. While patient-derived xenografts models (PDX, n=20) showed high similarity with patient tumor samples, in utero electroporation-based (IUE, n=2) mouse models did not fully recapitulate these BBB characteristics. Supratentorial ependymoma with ZFTA fusions revealed a higher transcriptional expression level of important tight junctions (e.g.Claudin5) compared to other groups and normal brain which was confirmed at protein level in respective PDX models by using both western blot and ultra-high content imaging. CONCLUSION: Analyses of important BBB markers revealed significant differences between molecular groups of ependymoma, which may partly explain drug resistance of ependymoma with ZFTA fusion caused by a low BBB permeability. BBB characteristics of corresponding models suggest that IUE and PDX models representing ZFTA fusion-driven tumors cannot equally be used within preclinical drug trials. Findings will be further validated in preclinical studies while molecular BBB characterization will be expanded to other brain tumors.
Transmission of monkeypox virus through sexual contact – A novel route of infection
Authors: Joseph Heskin, Amy Belfield, Charlotte Milne, Nicklas Brown, Yasmin Walters, Christopher Scott, Margherita Bracchi, Luke SP Moore, Nabeela Mughal, Tommy Rampling, Alan Winston, Mark Nelson, Sarah Duncan, Rachael Jones, D Ashley Price, Borja Mora-Peris
Journal: Journal of Infection (2022)
Clinical outcomes of patients with renal cell carcinoma and imperative indication to become anephric: Implications for multidisciplinary board evaluation
Authors: A. Nini, F. Trevisani, A. Bettiga, G. Fallara, G. Rosiello, A. Martini, L. Nocera, F. Belladelli, G. Baiamonte, W. Cazzaniga, I. Rowe, D. Canibus, G. Musso, F. Cei, C. Giancristofaro, A. Briganti, R. Bertini, A. Necchi, F. Montorsi, A. Salonia, A. Larcher, U. Capitanio
Journal: European Urology (2022)
Camrelizumab plus apatinib for patients with advanced mucosal melanoma: A prospective single-arm study.
Authors: Zhengyun Zou, Lianjun Zhao, Yu Ren, Huizi Sha, Baorui Liu
Journal: Journal of Clinical Oncology (2022)

9550 Background: Mucosal melanoma is a rare subtype in white populations, but the second most common subtype in Asian populations. This subtype is a more aggressive malignancy, with high risk of metastasis and death. Immune checkpoint inhibitor combined with anti-angiogenic agent has been investigated in many solid tumors, including some preliminary evidence (NCT03086174 and NCT04091217) in Chinese patients with advanced mucosal melanoma. This study investigated the efficacy and safety of camrelizumab plus apatinib in patients with advanced mucosal melanoma. Methods: In this prospective, single-arm study (ChiCTR1900023277), patients with inoperable stage III-IV or recurrent/metastatic mucosal melanoma and Eastern Cooperative Oncology Group performance status of 0-1 were enrolled. Patients received camrelizumab 200 mg once every 2 weeks and apatinib 500 mg once daily until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Results: Between April 2019 and January 2022, a total of 30 patients were enrolled (Table). As of January 2022, 21 patients had at least one efficacy assessment, and the median follow-up duration was 8.1 months. The ORR was 42.9%, including one (4.8%) patient with confirmed complete response, six (28.6%) with confirmed partial response (PR), and two (9.5%) with unconfirmed PR. The disease control rate (DCR) was 81.0%. The median progression-free survival was 7.2 months (95%CI, 5.8-not reached [NR]) in 21 patients, 7.7 months (95%CI, 5.8-NR) in 19 patients with first-line camrelizumab plus apatinib treatment, and 9.8 months (95%CI, 4.2-NR) in 11 patients without prior chemotherapy. The most common treatment-related adverse events in 27 patients with available safety data were fatigue (17 [63.0%]), hypertension (15 [55.6%]), and elevated transaminase (14 [51.9%]). No treatment-related deaths occurred. Exploratory analysis found a tendency that patients with high T cell receptor diversity had better prognosis. Higher frequencies of Vβ-Jβ (including Vβ5-8Jβ2-7, Vβ28J2-4 and Vβ12-5Jβ1-1) indicate better survival, and Vβ12-5Jβ1-1 is an independent factor after multivariate adjustment. Conclusions: Camrelizumab plus apatinib showed favorable ORR and DCR in patients with advanced mucosal melanoma, with an acceptable safety profile. Follow-up for survival outcomes is ongoing. Clinical trial information: ChiCTR1900023277. [Table: see text]
Identification of homologous recombination deficiency (HRD) by RAD51 in a tumor molecular profiling program for precision medicine.
Authors: Alba Llop-Guevara, Sara Arce-Gallego, Mafalda Oliveira, Sara Simonetti, Cristina Viaplana, Juan Francisco Grau, Carmen García-Duran, Isabel Pimentel, Paola Martínez, Jose Jimenez, Rodrigo Dienstmann, Paolo Nuciforo, Joan Carles, Ana Vivancos, Ana Oaknin, Cristina Saura, Susana Aguilar, Joaquin Mateo, Judith Balmaña, Violeta Serra
Journal: Journal of Clinical Oncology (2022)

3137 Background: Tumor molecular profiling by panel sequencing helps to identify candidate patients for precision oncology. Mutations in genes of the homologous recombination repair (HRR) pathway confer DNA repair deficiency and sensitivity to DNA damaging agents, such as PARP inhibitors (PARPi) or platinum-based drugs. RAD51 nuclear foci is a biomarker of functional HRR deficiency (HRD). We aimed to incorporate the RAD51 test in an academic molecular profiling program to identify HRD tumors beyond genetic testing. Methods: We included patients with metastatic breast cancer (TNBC, ER+ &lt;60y, 3rd line HER2+ BC), newly diagnosed high-grade epithelial ovarian cancer (HGOC) and metastatic and/or castration-resistant prostate adenocarcinoma (PC) undergoing tumor/germline genetic testing. A customized capture-based targeted sequencing of 450 genes was performed in FFPE tumor samples. RAD51 was manually stained by immunofluorescence and functional HRD was defined as RAD51 score ≤10%. Results: Between January 2021 and January 2022, tumor panel sequencing was performed in 279 tumors. Panel sequencing was informative in 264/279 (95%) samples and the RAD51 test was evaluable in 81/90 (90%). In total, 77 samples were evaluable for both tumor/germline sequencing and RAD51, namely 42 BC, 16 HGOC and 19 PC (Table 1). Functional HRD by RAD51 was observed in 15/77 (20%) cases. Panel sequencing identified 17/77 (22%) cases carrying HRR gene alterations, of which nine were confirmed as HRD by RAD51. In BC, 2/6 tumors with HRD by RAD51 did not carry a germline or tumor mutation in HRR genes. HRD tumor profiling triggered the germline analysis of one hereditary BRCA2 BC patient. Four g BRCA1/2 BC with HRD by RAD51 became HRR proficient (HRP) at PARPi progression. In addition, the RAD51 test identified 2/5 HGOC and 2/4 PC tumors as HRD despite not carrying a tumor HRR gene mutation. Conclusions: RAD51 testing is feasible in an established molecular profiling program and complements gene panel sequencing results by providing evidence of functional HRR status. In particular, the RAD51 test extends the identification of HRD tumors beyond those with HRR gene mutations and captures HRR restoration after PARPi treatment. We aim to expand the analysis of RAD51 to other tumor types.[Table: see text]
DIPG-12. Induced mitotic abnormalities associated with BMI-1 modulation sensitize diffuse intrinsic pontine glioma cells to ionizing radiation
Authors: Shiva Senthil Kumar, Deepak Mishra, Todd Mchugh, Rachid Drissi
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) remains an incurable childhood brain cancer with a median overall survival of less than 12 months, affecting 200-300 children annually in the United States. Hence, there is an unmet need for the development of novel and effective targeted therapies. BMI-1 is a subunit of the multimeric protein complex Polycomb repressor complex 1 (PRC1) implicated in self-renewal of normal and cancer cells, and in DNA damage signaling. We have previously identified BMI-1 as a potential therapeutic target in DIPG and have shown that BMI-1 is highly expressed in DIPG tumors regardless of H3K27 mutational status. Treatment of DIPG cells with PTC596, a small molecule initially identified as a BMI-1 modulator, and ionizing radiation (IR) impairs the kinetics of DNA damage response. in vivo, treatment with PTC596 alone delayed tumor growth kinetics and induced in-tumor apoptosis. However, we observed tumor regrowth once PTC596 treatment is completed or discontinued. In the present study, we evaluated the use of PTC596 in combination with IR. Our in vivo results indicate that PTC596 sensitizes DIPG cells to IR inducing a prolonged cell growth arrest 14 days post-treatment compared to IR or PTC596 alone. The effectiveness of this combination is currently evaluated in murine orthotopic DIPG models and the results will be presented. PTC596 is being tested in newly diagnosed children with DIPG and high-grade gliomas (NCT03605550). Data collected from this study will support the development of a novel therapy including PTC596 in combination with radiotherapy to treat children with DIPG.
Impact of ribociclib (RIB) dose modifications (mod) on overall survival (OS) in patients (pts) with HR+/HER2- advanced breast cancer (ABC) in MONALEESA(ML)-2.
Authors: Lowell L. Hart, Aditya Bardia, Joseph Thaddeus Beck, Arlene Chan, Patrick Neven, Erika P. Hamilton, Joohyuk Sohn, Gabe S. Sonke, Thomas Bachelot, Laura Spring, Fabienne Le Gac, Huilin Hu, Ming Gao, Michelino De Laurentiis
Journal: Journal of Clinical Oncology (2022)

1017 Background: The phase 3 ML-2, -3, and -7 trials all demonstrated consistent and statistically significant OS benefit with RIB (starting dose: 600 mg/d 3 wk on/1 wk off) vs PBO in pts with HR+/HER2− ABC. RIB dose mod (reductions and/or interruptions) when needed did not impact OS benefit with RIB + endocrine therapy (ET) in previous analyses of ML-3/-7. Here we present data on the effect of RIB dose mod on OS in postmenopausal pts with HR+/HER2− ABC in ML-2. Methods: ML-2 (NCT01958021) enrolled postmenopausal pts randomized 1:1 to first-line RIB + letrozole (LET) or PBO + LET. Landmark (LM) analyses of OS were performed to evaluate the association between dose reductions (yes vs no) and OS. Multiple LM times were considered to determine the sensitivity of the findings. As an alternative to LM analysis, a Cox proportional hazards model with a time-varying covariate was performed. Two time-dependent variables, dose reduction (with/without mod from 600 mg starting dose) and relative dose intensity 2 (RDI2), were included in the respective model as covariates to explore the association with OS. To account for differences in time to first dose mod, RDI2 reflects the post–dose mod period. Median (m) OS was obtained using a modified Kaplan-Meier method. Results: At data cutoff (June 10, 2021; m follow-up, 49.35 [range, 0-86.7] mo), 209 of 334 pts (62.6%) had ≥ 1 RIB dose reduction and 125 of 334 (37.4%) had 0 RIB dose reduction. LM analyses by dose reduction are presented (Table). mOS was 66.0 (95% CI, 57.6-75.7) mo in pts with ≥ 1 RIB dose reduction vs 60.6 (95% CI, 42.5-79.2) mo in pts with no RIB dose reductions (HR, 0.87 [95% CI, 0.65-1.18]). RDI2 was classified according to tertile: low (&lt; 64.27%), medium (64.27%-95.86%), and high (&gt; 95.86%). In pts with low, medium, and high RDI2, mOS was 62.6 (95% CI, 50.0-80.7) mo, 63.9 (95% CI, 48.8-not reached [NR]) mo, and 65.3 (95% CI, 50.5-NR) mo, respectively (HR low vs high, 0.99 [95% CI, 0.69-1.42]; HR medium vs high, 0.97 [95% CI, 0.62-1.38]). Conclusions: In this exploratory analysis of ML-2, OS benefit was maintained in pts with HR+/HER2− ABC who required mod from the recommended starting dose of RIB (600 mg/d 3 wk on/1 wk off). No relationship was observed between OS and RIB dose reduction or RDI2; OS benefit with RIB was observed in all groups. Clinical trial information: NCT01958021. [Table: see text]
The impact of patient-reported outcomes in cancer patients in Croatia.
Authors: Dragan Trivanovic, Boris Kopic, Anuska Budisavljevic, Irena Hrstic
Journal: Journal of Clinical Oncology (2022)

e18659 Background: Perception of symptoms is essential for optimal cancer care and improving the quality of life but an inappropriate interpretation may lead to treatment outcomes failure or may leave the patients undertreated. This variation in the perception of adverse events (AEs) can lead to wrong assumptions and potentially unnecessary hospitalizations (H) or emergency room visits (ERV). Methods: Patients considered for inclusion were 18 years of age or older receiving systemic therapy and were able to read and understand questionnaire via tablet computers. All patients had a verified diagnosis of malignant disease of breast (31%), lung (17%), colorectal (16%), hematological (8%) or other site cancers (28%). Patients were asked on the same day as physician assessment, to complete 10 PRO-CTCAE symptoms (including fatigue, pain, nausea, vomiting, diarrhea, dysgeusia, appetite, sleep disturbance, fever, and alopecia). Participants remained on study until discontinuation of cancer treatment, withdrawal, or death. Informed consent was obtained from all patients and the study was approved by the institutional review board of the General Hospital Pula, Croatia. Concordance of symptoms reporting between patients and health care providers at the individual level was compared, and intraclass correlation coefficients were computed by a two way mixed effect model and an absolute agreement definition. Univariate and multivariate COX proportional hazard models adjusted for covariates including age, gender, cancer type and performance status were constructed for unplanned H and ERV. Results: The median age of 308 included patients in this trial was 62 years. Cohen's coefficient of agreement that corrects for chance for AEs gr. 1-5 and AEs gr. 3-4 was 0.115 (95%, CI, 0.15 to 0.02), indicating only slight agreement and 0.320 (95%, CI, 0.428 to 0.448) indicating fair agreement, respectively. Physicians underestimated symptoms at the group level (p &lt; 0.013) for all symptoms. The highest level of agreement was found for pain but fatigue and alopecia were most underestimated. The median times of follow-up were 13 months, and 8,1 % of patients had H or ERV. Female patients had worse PRO scores, with higher levels of pain, fatigue, and alopecia across disease groups. In multivariate analysis, patient symptoms was not predictive, but we noticed trend for higher patient reports of pain (p = 0.05) for unnecessary H or ERV. Conclusions: The failure of the physician to identify a substantial number and severity of symptoms identified by the PRO instrument is not surprising considering the published experience in clinical trials. To our knowledge, this is the first such analysis aimed specifically at examining the reliability of physician identification of AEs in a real world practice in Croatia. The incorporation of PRO measures into routine practice might help to avoid unnecessary hospitalizations and emergency room visits. Clinical trial information: 2019-000855-15.
Artificial engineering of the protein corona at bio-nano interfaces for improved cancer-targeted nanotherapy
Authors: Suliman Khan, Majid Sharifi, Jason P. Gleghorn, Mohammad Mahdi Nejadi Babadaei, Samir Haj Bloukh, Zehra Edis, Mohammadreza Amin, Qian Bai, Timo L.M. ten Hagen, Mojtaba Falahati, William C. Cho
Journal: Journal of Controlled Release (2022)
NEJ043: A phase 2 study of atezolizumab (atezo) plus bevacizumab (bev) plus carboplatin (carbo) plus paclitaxel (pac; ABCP) for previously treated patients with NSCLC harboring <i>EGFR</i> mutations (EGFRm).
Authors: Naoki Furuya, Satoshi Watanabe, Atsushi Nakamura, Jun Shiihara, Ichiro Nakachi, Hisashi Tanaka, Mika Nakao, Koichi Minato, Masahiro Seike, Shinichi Sasaki, Akira Kisohara, Susumu Takeuchi, Ryoichi Honda, Kei Takamura, Hiroshi Kagamu, Kenichi Yoshimura, Toshiaki Kikuchi, Kunihiko Kobayashi
Journal: Journal of Clinical Oncology (2022)

9110 Background: Previous studies have demonstrated poor clinical outcomes of patients (pts) with EGFRm NSCLC treated with PD-1/PD-L1 inhibitors. However, a recent subgroup analysis of the IMpower150 trial suggested the effectiveness of ABCP in NSCLC with EGFRm. The aim of this study is to further evaluate efficacy and safety of ABCP in patients with EGFRm NSCLC. Methods: This single-arm multicenter phase 2 study included pts with nonsquamous NSCLC harboring sensitizing EGFRm with prior EGFR-TKI therapy. Pts received the combination dose of atezo 1200 mg, bev 15 mg/kg, carbo AUC 6 mg/mL/min and pac 175 mg/m 2 every 3 weeks up to 4 cycles followed by atezo plus bev until loss of clinical benefit. The primary endpoint was PFS by extramural review (ER). The key secondary endpoints included OS, ORR, DoR, relative dose intensity of pac, and safety. Results: 60 pts were enrolled (median age 68 y [40–74 y], 67% were female, 55% were Ex19del and 40% were L858R). At data cutoff (November 30, 2021), median follow-up was 12.8 months in the ITT population. Median cycles of induction and maintenance therapy were 4 and 9, respectively. Median PFS was 7.4 month (95% CI, 5.7-8.2) and median OS was 18.9 month (95% CI, 13-not reached). Confirmed ORR by ER was 56% (95% CI, 43-69) and median DoR was 7.1 months (95% CI, 4.9-9.8). T790M was associated with a favorable PFS and response to the combination therapy (PFS 8.1 vs 6.8, ORR 71% vs 50%). Relative dose intensity of pac was 84%. Grade ≥3 adverse events (AEs) were reported in 92% of pts and the most common grade ≥3 AE was neutropenia (63%). Interstitial lung disease occurred in one patient (2%). AEs leading to treatment discontinuation occurred in 12% of pts. Conclusions: NEJ043 study showed that the median PFS of ABCP was 7.4 months with good tolerability. We will continue to investigate the tail plateau phenomenon of PFS and OS to conclude the clinical efficacy. Clinical trial information: 031190066.